Pathogenesis of Acquired Aneurysms of the Abdominal Aorta

General review

Pathogenesis of Acquired Aneurysms of the Abdominal Aorta Samy Anidjar, MD, Edouard Kieffer, MD, Paris, France

The incidence of abdominal aortic aneurysm has recently increased. There is still no accurate definition of abdominal aortic aneurysm. The diameter of abdominal aortic aneurysms is the only factor permitting evaluation of the risk of rupture of aneurysms whose growth remains unpredictable. Abdominal aortic aneurysm is a multifactorial disease associated with aortic aging and atheroma. It differs from stenotic disease by the intensity of degenerative or destructive phenomena in the media. Particular hemodynamic conditions in the infrarenal abdominal aorta seem to enhance the development of aneurysm at this level. While certain constitutional anomalies of the extracellular matrix of proteins seem to enhance the development of abdominal aortic aneurysm, protease activity of as yet undetermined origin also seems to play a prominent role. Family cases of abdominal aortic aneurysms have been reported but the mechanisms responsible remain to be determined. Several genetic markers have been suggested. The most reliable marker of aortic aneurysm is arteriomegaly. (Ann Vasc Surg 1992;6:298-305). KEY WORDS:

Abdominal aorta; aneurysms; abdominal aortic aneurysm.

Aneurysm of the abdominal aorta (AAA) is a degenerative disease of the aortic wall occurring essentially during the sixth, seventh, and eighth decades of life. According to several studies made in the United Kingdom and the United States, the incidence of AAA can reasonably be said to be at least 3% in the general population 50 years or older [1-5]. The incidence of AAA is increasing. In the United States, AAA ranks thirteenth among the causes of death [6], with 1.2% of males and 0,6% of females aged 65 or more dying of AAA in 1984 [7]. Aneurysm of the abdominal aorta is much more frequent in men than in women; the male/female From the Service de Chirurgie Vasculaire, Groupe Hospitalier PitiO-SalpOtri~re, Paris, France. Reprint requests: Samy Anidjar, MD, Service de Chirurgie Vasculaire, Groupe Hospitalier Piti(-Salp~triOre, 47-83 bd de l'HOpital, 75651 Paris C~dex 13, France.

ratio ranges from 3:1 to 8:1 [1,8,9]. This ratio, however, decreases with age. During the last three decades, there has been a linear increase in the incidence of AAA in the United States [I0,11], England and Wales [12], Scotland [13], and Australia [14]. Improvement in means of diagnosis and increasing interest in this pathology are possible but only partial explanations for upswing of AAAs. Sonography made its appearance in the 1960s and has contributed in major ways to improved diagnosis. In the United States, mortality due to AAA increased by 300% between 1951 and 1968. Beginning in 1968, the number of deaths due to AAA remained on a plateau without decreasing until 1981 [10]. Conversely, during this same period, death due to coronary artery disease [15] and vascular cerebral accidents [16] decreased by 25%. In England and Wales, the number of deaths by AAA

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increased before 1950 [17]. In a study conducted in Rochester, New York, the number of new cases of AAA increased from 8.7 to 36.5 per 100,000 habitants between 1951 and 1980. During this same period, the incidence of rupture of the 296 diagnosed AAAs was 20.3% [18].

N A T U R A L HISTORY OF AAA Aneurysms of the abdominal aorta are usually asymptomatic until rupture, which represents the major evolutive risk [18,19]. Overall and operative mortality of ruptured AAA is approximately 80% and 40%, respectively [20-22]. This contrasts sharply with the satisfactory results of most published series of elective surgery in AAA, for which operative mortality is less than 5% [23-26]. The indication for operation in A A A therefore depends essentially on the risk of rupture. Until now, only the point where the diameter of the A A A reaches a certain size has been correlated with the risk of rupture [19,27,28]. Most authors agree that 4-5 cm represents the limit above which the risk becomes substantial. Moreover, aneurysmal growth seems to follow an exponential curve. The rate of growth (unpredictable) is not function of the initial diameter of AAA, age, or sex of the patient, and is not correlated with the risk of rupture [29]. Evaluation of the risk of rupture of small AAAs remains very difficult. In Darling's autopsy study the incidence of rupture of AAA whose diameter was 4 cm or less was 9.5% [27]. In a study conducted in a population from Rochester, New York, Nevitt and associates [30] recently showed that the incidence of rupture for AAA of less than 5 cm was zero at five years. Although in disagreement, both of these studies are subject to criticism. In the former, the diameter was measured on aortic specimens which were not fixed; their diameters were therefore most likely smaller than their in vivo size. In the latter, use of the term aneut2esm is questionable, as 31% of lesions measured less than 3.5 cm in diameter.

Redefining AAA

Until recently, definition of a AAA has been a problem. Now the Ad Hoc Committee on Reporting Standards of the SVS (Society for Vascular Surgery) and the ISCVS (North American Chapter of the International Society for Cardiovascular Surgery) proposed to define arterial aneurysm as "permanent localized dilatation of more than 50% of the normal diameter of the a r t e r y " [31]. However, for each individual, the diameter of the infrarenal aorta varies according to weight, height, blood pressure, and, obviously, the method of measurement. It

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seems, therefore, more logical to consider each individual from his or her own reference point and to define infrarenal AAA based on the diameter of the supraaneurysmal interrenal aorta. Therefore, for Crawford, a AAA is present when the diameter of the infrarenal aorta is at least 1.5 times that of the interrenal aorta [32]. However, confusion is increased by the existence of several anatomical forms of AAA. For example, it is not known whether "aneurysmal dystrophia" or "pseudoaneurysms'" of the infrarenal abdominal aorta, characterized by very localized and staged dilatations, have the same evolutive potential as the diffuse aneurysmal dilatations of a segment or the entire infrarenal aorta or whether they belong to the same nosological category.

Hemodynamics and mechanical factors

The infrarenal abdominal aorta is obviously a preferential site for the development of aneurysm. Several anatomical and physiological factors seem to enhance the development of aneurysm at this level. The human abdominal aorta contains fewer lamellar units than its diameter and thickness would lead one to expect. The lamellar unit is the elementary structure of the media. Schematically, the elastic lamellae are arranged in concentric fibrillary leaves separated by smooth muscle cells. In mammals, the number of units is directly related to the diameter and the thickness of the aorta wall [33]. An aorta 16 mm in diameter with a wall 0.8 mm thick should contain approximately 50 lamellar units. In reality, the human aorta of these dimensions contains only 30 such units, which increases the mural tension per lamellar unit. Moreover, the aorta tapers off as its rigidity increases (reflecting an increase in collagen and decrease in elastin) from the root distally [34,35]. Contrary to the thoracic aorta, the pulse wave is reflected while blood flow slows down in the infrarenal abdominal aorta, which increases the time of contact between atherogenous particles and the aortic endothelium and promotes the development of atheroma [36]. At this level, increased systolic pressure and decreased diastolic pressure are responsible for the large pressure variations of the entire vascular tree [34,37,38]. Lastly, there is no vasa vasorum in the human abdominal aorta, which means that nutrition is provided by simple diffusion from the aortic lumen [39,40]. Increased mural gradient of diffusion due to atheroma further reduces the capacity of the aortic wall to heal. The overall result is that these mechanisms enhance the mutilation and thinning of the wall, which leads to progressive dilatation and, ultimately, rupture.

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Reaction of the aortic wall to atheroma

Most will agree that the combination of local factors, atheroma, and "aging" of the aorta contribute to the prevalence of infrarenal abdominal aorta aneurysms; it remains to be determined why this multifactorial context, present in fact in all individuals, can also lead to aortic stenosis rather than aneurysm. "Stenosing" disease is characterized by development of intimal lesions while "aneurysmal" disease is characterized by the intensity of destruction of the media [41]. Aneurysmal disease occurs at a more advanced age and involves men more often than women [42]. Paradoxically, experimental atheroma models rarely lead to aneurysm [43-45], and several authors have attempted to demonstrate that atherosclerosis and aneurysmal disease are two entirely different pathological processes without any relationship [42]. In fact, stenosis and aneurysm represent two types of responses of the arterial wall to atheroma [41]. Hypothetical constitutional protein diseases of the extracellular matrix and other genetic factors could accelerate the course of atheroma to the development of aneurysm. Up until the present time, no study has shown that the risk factors of atherosclerosis were any different in the event of aneurysmal disease [46--48]. Destruction of the media

The fundamental histopathological characteristic of AAA is the importance of destructive or degenerative phenomena in the media [49-51], which underscores the apparent absence of regeneration or repair capacity of the aortic wail. Compared with normal aorta, elastic fibers and muscle cells are rare, and in some areas the media is completely absent [51]. Increased collagen content in the aneurysmal wall is due not only to the disappearance of elastic fibers but also to neosynthesis of collagen fibers as a response to remodeling of the aortic wall under the effects of mural hemodynamic stress [51]. Determinants of aneurysmal dilatation

The determinants of aneurysmal dilatation are intricate. While it is true that elastic fibers are rare in the AAA wall [52,53], in vitro [54] and in vivo [35] disappearance of elastic fibers promotes only slight dilatation. Aneurysmal dilatation therefore necessarily implies a phenomenon of fragmentation and degradation of collagen fibers [56,57]. Schematically, the loss of elastic fibers is responsible for an initial but small degree of dilatation. Gradual remodeling of the aortic wall under mural and other stress related to collagenolysis leads to aneurysmal dilatation in the larger diameters [54-61]. As the aorta dilates, it becomes cylindrical, and this corn-

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pensatory response leads to reduced parietal tension [54,61]. Moreover, onset of aneurysmal dilatation provokes turbulence in circulatory flow and leads to development of mural thrombosis. In contrast to what occurs in collagen metabolism, these phenomena underscore the apparent absence of elastin neosynthesis. It seems that the biosynthesis of elastic fibers occurs only in the early phases of ontogenesis and postuterine development. Even though possible in the adult human being, it would result in a haphazard and nonfunctional fiber orientation and would be so weak that it would not be measurable by present methods [62,63].

Constitutional anomalies of proteins in the extracellular matrix

Several authors have attempted to show that constitutional protein anomalies in the extracellular matrix can predispose to the development of AAA. While in Marfan's disease the elastic fibers in the aortic wall are rare and fragmented, we now know that the anomaly is not created at the level of the genes coding for elastin or collagen [64-66] but rather at the level of the gene coding for fibrillin. A recent study showed an important decrease in the quantity of fibrillin in connective tissue [67]. This glucoprotein is one of the components of the microfibrillas which envelope the elastic fibers. In Marfan's disease this could represent enhancement of the degradation of elastic fibers by elastases. As regards collagen, a recent study detected a mutation of the coding gene of type III procollagen in the members of a family who died of aortic rupture [68]. This mutation is located at the level of the codon for the amino acid in the 619 position on the alpha 1 chain which is arginine rather than glycin. This leads to the formation of an abnormal triple helix of collagen modifying the mechanical qualities of the collagen fiber. Surprisingly, this anomaly has little effect before the fourth to sixth decades of life. However, caution must be exercised in the interpretation of results, as aortic rupture was secondary to dissection and not to aneurysm, which terms were misused by the authors in this study. This is similar to what is observed in type IV Ehlers-Danlos disease in which the type III collagen fibers are decreased in number or even missing [69]. During the course of this disease, true aortic dilatation is not observed, whereas aortic ruptures or dissections do occur [70]. While several authors have observed families with AAA with decreased type III collagen, this was not confirmed by the recent study of Rizzo and associates [51 ]. It is therefore very difficult to demonstrate that degenerative AAA may be due to extracellular

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matricial protein constitutional anomalies, even in the familial forms. However, while it remains possible, said anomalies do not involve elastin or collagen fibers themselves, but rather smaller proteins, as is the case with Marfan's syndrome. One might assume that these anomalies could increase the fragility of elastin or collagen leading to aneurysmal degeneration of the aortic wall. Arteriomegaly is the only morphological anomaly clearly associated with the development of aneurysms as a promoting factor [71-75]. This entity is characterized by dilatation and lengthening of one or several arterial vessels with considerable rarefaction of elastic fibers, which are replaced by collagen fibers. The disappearance of elastic fibers seems to be the first step toward true aneurysmal dilatation. As yet, the etiology of arteriomegaly remains unknown. Patients with AAA may schematically be classified into two groups: the first has arteriomegaly, for which AAA is often just a part of multiple aneurysmal disease, while the other is without arteriomegaly and AAA is most often isolated. This underscores the multifactorial character of aneurysmal pathogenesis. Arteriomegaly seems to be an anomaly which promotes the development of aneurysms while hemodynamics are responsible for the development of aneurysms at the level of the infrarenal aorta. The role of proteases and inflammatory cells

Irrespective of the presence or absence of anomalies promoting degenerative phenomena in the aortic media, protease activity has to intervene at some stage in the disappearance of elastic fibers and remodeling of the aneurysmal wall. Elastin is an insoluble, fibrous protein. It is very robust and extremely resistant to several physical and chemical agents. Several clinical studies have clearly demonstrated the presence of elastase and collagenase activities in the wall of the AAA, thereby lending support to the preceding hypothesis [49,52,53,76]. Moreover, only in vivo infusion of proteases can induce experimental aneurysms in the animal [59]. The principal source of protease is in inflammatory, polymorphonuclear and macrophage cells [7779]. These cells are called elastophages, and their role has been clearly demonstrated in Horton's and Takayasu's disease. However, their role in the degenerative pathology of AAA remains to be defined. Many other questions remain. Although inflammatory cells are very often found in the adventitia of AAA walls [80,81], their presence has never been correlated with protease activity or the intensity of degenerative phenomena. In addition, proteases extracted from the walls of AAAs are difficult to

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analyze. They are similar in character to leukocyte elastase and macrophage stromelysin. Moreover, the presence of collagenase activity has been associated with rupture of AAA but it is not known whether the two were related [51]. Lymphocytes are equally present in the wall of AAAs [82]. They may play a role in the recognition of degradation products of the extracellular matrix. The synthesis of antielastin antibodies could enhance the degradation of elastic fibers [83,84]. Therefore, while inflammation is the primary phenomenon in the aneurysmal formation of certain cases of segmentary panarteritis, it could represent a reactive phenomenon in degenerative AAA and aggravate the destruction of the aortic wall through the intermediary of protease secretion and immunopathological phenomena. Aside from protease activity directly related to the presence of inflammatory cells, a role for soluble proteases has also been suggested [85]. It should be noted that a very close in vivo equilibrium exists between proteases and antiproteases. The physiological inhibitors of leukocyte elastase and stromelysin are alpha-l-antitrypsin and the tissular inhibitor of metailoprotease (TIMP). Several authors have attempted to show that a deficit in antiproteases could promote development of substantial protease activities within the aortic media [52,85]. It is difficult, however, to conceive of a systemic deficit in the proteases/antiproteases equilibrium. The phenomena which lead to protease activities in the aortic wall are obviously limited in the infrarenal portion of the abdominal aortic wall. On the other hand, local proteolytic activity acts at the systemic level by increasing the amount of circulating antiproteases as shown by Campa and colleagues [53]. This is a phenomenon of adaptation by means of which the organism protects itself against the diffusion of protease activity. In terms of the aortic intima, monocytes, macrophages, and spumous cells within the atheromatous plaque could be responsible for the secretion of certain substances which might contribute to the degenerative phenomena of the aortic wall [86]. These activated cells could indeed secrete proteases (elastase, collagenase, mucopolysaccharidases) responsible for the degradation of the extracellular matrix [87,88]. Furthermore, monocytes and macrophages secrete superoxide ions and free radicals which provoke the oxidation of low density lipoproteins (LDL), thus enhancing their capture by the macrophages, which have a direct toxic effect on endothelial and smooth muscle cells [89]. Macrophages also secrete interleukin-1 and tumor necrosis factor which induce tissular catabolism and are T-lymphocyte activators. Whereas macrophages are abundant in atheroma plaque [90], notably in the center which is rich in lipids, T-lymphocytes are equally present at the level of the plaque

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shell and subintimal layer [91]. Approximately one third of these lymphocytes are activated and could participate in immunopathological phenomena. Last, lymphocytes secrete the gamma interferon which inhibits collagen synthesis and increases macrophage elastase activity [92]. Calcium overload

Calcium deposits could contribute to aneurysmal degeneration of the aortic wall. Calcium might act as an inflammatory agent and promote the afflux of macrophages [93]. Moreover, calcium overload can be responsible for major functional disorders in smooth muscle cells, which contribute to aneurysmal degeneration of the media [94].

The occurrence of this type of accident is similar to what is observed in type IV Ehlers-Danlos disease in which a mutation of the coding gene for type III procollagen has equally been found. Constitutional arterial fragility exists in this disease and is responsible for mechanical accidents, including intimal lacerations, arterial tears, and ruptures. Prior to the accident, aneurysmal dilatation was never found in any of these cases. These diseases constitute a different nosological entity. As regards true degenerative AAA, several authors have attempted to delineate genetic markers. A significant relationship was found in patients with AAA and blood groups MN and Kell+ [116,117] and the 2-1 haptoglobin phenotype [118]. In the presence of these markers, the risk of developing an AAA is increased twofold. Paradoxically, there is no family grouping with respect to these markers.

Copper deficiency

Copper deficiency could play a role in the pathogenesis of aneurysmal pathology by affecting the maturation of elastic and collagen fibers. Certain authors have attempted to demonstrate that AAA could be associated with copper deficits [95,961]. In fact, copper deficiency has been shown experimentally to play a role during the critical phases of maturation and development of elastic and collagen fibers [9%100] (early phases of ontogenesis and postuterine development) but this remains difficult to demonstrate in human beings. Familial forms of AAA

Underlying pathology mechanisms not withstanding, it seems as though AAA can occur in family groups [101-108]. The risk of developing an AAA is higher in first degree relatives of a patient with AAA. Although the hypothesis of genetic transmission of aneurysmal disease is presently far from well established, several modes of transmission have been suggested including sex-related [109,110], autosomal dominant [I09,110], multiple factorial [109-Ill], and autosomal recessive [112] transmission. According to this hypothesis, when AAA exists, family screening could be of value. Two studies of this type were made in Sweden and in the United States. The Swedish study included 87 brothers and sisters (mean age 63 years) of 32 patients with AAA [113]. Abdominal aorta "dilatation" was found in 13 (10 men and 3 women). The American study found 10 aneurysms in family members of 43 patients having undergone resection for AAA [114,115]. In the study of Kontussaari and coworkers, the pathohistological examination of the aortic wall of two members of the same family who died from aortic rupture showed that in fact, the patients had aortic dissections rather than true aneurysms [68].

Risk factors of atherosclerosis

As concerns risk factors of atherosclerosis, certain markers are associated with AAA but none of them seem to be truly discriminative. Differences have been noted at the level of circulating lipids [119,120]. Autopsy studies have demonstrated a relationship between AAA and tobacco abuse [12!]. Arterial hypertension is probably a promoting factor in the development and rupture of AAA [19,29,122]. Moreover, the incidence of AAA seems higher in patients with severe atheroma [9]. Arteriomegaly is an excellent marker of aneurysmal disease [71,72].

CONCLUSION The pathogenesis of AAA is multifactorial as attested to by its myriad anatomic and clinical forms. Several studies have attempted to demonstrate a prominent role for genetic factors in aneurysmal development, but none of the genetic markers have clearly been shown to be responsible. The only morphological and histological disease (or anomaly) clearly associated with AAA is arteriomegaly, but this entity is found only rarely in patients with AAA. Most often, patients with AAA do not have any discriminating signs aside from the fact that their mean age is higher. While certain constitutional protein anomalies of the extracellular matrix seem to enhance the development of AAA, degenerative or proteolytic activity factors are clearly implicated. Aside from primitive inflammation of the aorta, inflammatory cells could participate in the aneurysmal pathogenesis by aggravating the degenerative phenomena and thus contributing to progress of lesions. While family forms of AAA have been described, analysis of

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these determinant factors is complex and should not be exclusively oriented to genetic factors.

REFERENCES 1. ALLEN PIM, GOUREVITCH D, M C K I N L E Y J, et al. Population screening for aortic aneurysms. Lancet 1987;2: 736. 2. COLLIN J, ARAUJO L, WALTON J, et al. Oxford screening programme for abdominal aortic aneurysm in men aged 65 to 74 years. Lancet 1988;2:613-615. 3. SCOTT RAP, ASHTON H, SUTTON GLJ. Ultrasound screening of a general practice population for aortic aneurysm. Br J Surg 1986;73:318. 4. GORE I, H1RST AE Jr. Arteriosclerotic aneurysms of the abdominal aorta: a review. Prog Cardiovasc Dis 1973;16: 113-149.

5. HALPERT B, WILLMS RK. Aneurysms of aorta. Arch Pathol 1962;74:163-168. 6. SILVERBERG E, LUBERA JA. Cancer statistics, 1983. American Cancer Society, New York. 7. National Center for Health Statistics. Vital Statistics of the US, 1984, vol. 2: Mortality part A. US Dept of Health and Human Services, Hyattsville, MD. 8. TWOMEY A, TWOMEY E, WILKINS RA, et al. Unrecognised aneurysmal disease in male hypertensive patients. tnt Angiol 1986;5:269-273. 9. ALLARDICE JT, ALLWRIGHT G J, WAFULA JMC, et al. High prevalence of abdominal aortic aneurysm in men with peripheral vascular disease: screening by ultrasonography. Br J Surg 1988;75:240-242. 10. MELTON LJ, BICKERSTAFF LK, HOLLIER LH, et al. Changing incidence of abdominal aortic aneurysms: a population-based study. Am J Epidemiol 1984;120:37%386. 11. LILIENFIELD DE, GUNDERSON PD, SPRAFKA JM, et al. Epidemiology of aortic aneurysms: t. Mortality trends in the United States, 1951 to 1981. Arteriosclerosis 1987;7:637-643. 12. FOWKES FGR, MACINTYRE CCA, RUCKLEY CV. Increasing incidence of aortic aneurysms in England and Wales. Br Med J 1989;298:33-35. 13. NAYLOR AR, WEBB J, FOWKES FGR, et al. Trends in abdominal aortic aneurysm surgery in Scotland (19711984). Eur J Vasc Surg 1988;2:217-221. 14. CASTLEDEN WM, MERCER JC, and members of the West Australian Vascular Service. Abdominal aortic aneurysms in Western Australia: descriptive epidemiology and patterns of rupture. Br J Surg 1985;72:109-I 12. 15. FEIBLEIB M, THOM T, HAVLIK RJ. Decline in coronary heart disease mortality in the United States. Atherosclerosis Rev 1982;9:29--41. 16. GARAWAY WM, WHISNAT JP, FURLAN AJ. The declining incidence of stroke. N Engl J Med 1979;300:44% 452. 17. MANIGLIA R, GREGORY JE. Increasing incidence of arteriosclerotic aortic aneurysms: analysis of six thousand autopsies. Arch Path 1952;54:298-305. 18. BICKERSTAFF LK, HOLLIER LH, VAN PEENEN FJ, et al. Abdominal aortic aneurysms: the changing natural history. J Vasc Surg 1984;1:6-12. 19. CRONENWETT JL, MURPHY TF, ZELENOCK GB, et al. Actuarial analysis of variables associated with rupture of small abdominal aortic aneurysms. Surgery 1985;98:472483. 20. HOFFMAN M, AVELONE JC, PLECHA FR, et al. Operation for ruptured abdominal aortic aneurysms: a community wide experience. Surgery 1982;91:597-602. 21. DONALDSON MC, ROSENBERG JM, BUCKMAN CA.

303

Factors affecting survival after ruptured abdominal aortic aneurysms. J Vasc Surg 1985;2:564-570. 22. MEYER AA, AHLQUIST RE, TRUNKEY DD. Mortality from ruptured abdominal aortic aneurysms. A m J Surg 1986;152:27-33. 23. CRAWFORD ES, SALEH SA, BABB III JW, et at. Infrarenal abdominal aortic aneurysm: factors influencing survival after operation performed over a 25 year period. Ann Surg 1981;193:699-709. 24. WHITTEMORE AD, CLOWES AW, HECHTMAN HB, et al. Aortic aneurysm repair reduced operative mortality associated with maintenance of optimal cardiac performance. Ann Surg 1980;120:414-421. 25. THOMPSON JE, HOLLIER LH, PUTMAN RD, et al. Surgical management of abdominal aortic aneurysms. Ann Surg 1975;181:654-660. 26. JOHNSTON KW, SCOBIE TK. Multicenter prospective study of nonruptured abdominal aortic aneurysms. I. Population and operative management. J Vasc Surg 1988;7:6981. 27. DARLING RC, MESSINA CR, BREWSTER DC, et al. Autopsy study of unoperated abdominal aortic aneurysms. The case for early resection. Circulation (Cardiovasc Surg, suppl. 2) 1977;56:161-164. 28. BERNSTEIN EF, CHAN EL. Abdominal aortic aneurysm in high-risk patients. Ann Surg 1984;200:255-263. 29. CRONENWETT JL, SARGENT SK, WALL MH, et al. Variables that affect the expansion rate and outcome of small abdominal aortic aneurysms. J Vasc Surg 1990;11: 260-269. 30. NEVITT MP, BALLARD DJ, HALLETT JW. Prognosis of abdominal aortic aneurysms. A population based study. N Engl J Med 1989;321:1009-1014. 3I. JOHNSTON KW, RUTHERFORD RB, TILSON MD, et al. Suggested standard for reporting on arterial aneurysms. J Vasc Surg 1991;13:444--450. 32. CRAWFORD ES, HESS KR. Abdominal aortic aneurysm. N Engl J Med 1989;321:1040-1042. 33. WOLINSKY H, GLAGOV S. A lamellar unit of aortic medial structure and function in mammals. Circ Res 1967; 20:9%111. 34. PATEL DJ, DEFREITAS FM, GREENFIELD JC, et al. Relationship of radius to pressure along the aorta in living dogs. J Appl Physiol 1963;18: I 111-1117. 35. HARKNESS MLR, HARKNESS RD, MC DONALD DA. The collagen and elastin content of the arterial wall in the dog. Proc Roy Soc Med 1957;146:541-551. 36. ZARINS CK, GLAGOV S, GIDDENS DP, et al. Hemodynamic factors and atherosclerotic change in the aorta. In: BERGAN J J, YAO JST (eds). Aortic" Surge~'. Philadelphia: W.B. Saunders, 1988, pp 17-25. 37. MC DONALD DA. Regional pulse-wave velocity in the arterial tree. J Appl Physiol 1968;24:73-78. 38. MC DONALD DA. Blood Flow in Arteries. Williams and Wilkins. Baltimore, 1974. 39. WOLINSKY H, GLAGOV S. Nature of species differences in the medial distribution of aortic vasa vasorum in mammals. Circ Res 1967;20:409-421. 40. HEISTAD DD, MARCUS ML, MARTINS JB. Effects of neural stimuli on blood flow through vasa vasorum in dogs. Circ Res 1979;45:615--620. 41. ZARINS CK, GLAGOV S. Aneurysms and obstructive plaques: differing local responses to atherosclerosis. In: BERGAN JJ, YAO JST (eds). Aneurysms: Diagnosis and Treatment. New York: Grune and Stratton, 1984, pp 6142. 42. TILSON MD, STANSEL HC. Differences in results for aneurysms vs occlusive disease after bifurcation grafts. Arch Surg 1980;115:1173-1175. 43. DE PALMA RG, KOLETSKY S, BELLON EM. Failure of regression of atherosclerosis in dogs with moderate cholesterolemia. Atherosclerosis 1977;27:297-310. 44. STRICKLAND HL, BOND MG. Aneurysms in a large

304

45. 46. 47.

48. 49. 50.

51. 52. 53. 54.

55. 56. 57.

58. 59. 60. 61. 62. 63.

64. 65. 66. 67.

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colony of squirrel monkeys. Lab Anita Sci 1983;33:589592. ZARINS CK, GLAGOV S, VESSELINOVITCH D. Aneurysm formation in experimental atherosclerosis: relation to plaque evolution. J Vasc Surg 1990;12:246-256. THURMOND AS, SEMLER HJ. Abdominal aortic aneurysm: incidence in a population at risk. J Cardiovasc Surg 1986;27:457. CABELLON S, MONCRIEF CL, PIERRE DR, et al. Incidence of abdominal aortic aneurysm in patients with atheromatous arterial disease. A m J Surg t983;146:575576. ROSEN AB, DE PALMA RG, VICTOR Y. Risk factors in peripheral atherosclerosis. Arch Surg 1973;107:303-306. POWELL JT, G R E E N H A L G H RM. Cellular, enzymatic and genetic factors in the pathogenesis of abdominal aortic aneurysms. J Vasc Surg 1989;9:297-304. SUMNER DS, HOKANSON DE, STRANDNESS DE. Stress-strain characteristics and collagen-elastin content of abdominal aortic aneurysms. Surg Gynecol Obstet 1970; 130:459-466. RIZZO RJ, M C C A R T H Y WJ, DIXIT SN, et al. Collagen types and matrix protein content in human abdominal aortic aneurysms. J Vasc Surg 1989;10:365-373. COHEN JR, M A N D E L L C, CHANG JB. Elastin metabolism of the infrarenal aorta. J Vasc Surg 1988;7:210-214. CAMPA JS, G R E E N H A L G H RM, POWELL JT. Elastin degradation in abdominal aortic aneurysms. Atherosclerosis' 1987;65:13-21. DOBRIN PB, BAKER WH, GLEY WC. Elastolytic and collagenolytic studies of arteries: implications for the mechanical properties of arteries. Arch Surg 1984;119:405409. ANIDJAR S, DOBRIN PB, CHEJFEC G. Etude exprrimentale des d6terminants de la dilatation anrvrysmale. Ann Chir Vasc 1992; in press. MENASHI S, CAMPA JS, G R E E N H A L G H RM, et al. Collagen in abdominal aortic aneurysm: typing, content and degradation. J Vasc Surg 1987;6:578-582. ROSENBERG N, HENDERSON J, DOUGLAS JF, et al. The use of arterial implants prepared by enzymatic modification of arterial homografts. II. The physical properties of the elastica and collagen components of the arterial wall. Arch Surg 1957;74:89-95. DOBRIN PB, SCHWARCZ TH, BAKER WH. Mechanisms of arterial and aneurysmal tortuosity. Surgery 1988; 104:568-571. ANIDJAR S, SALZMANN JL, GENTRIC D, et al. Elastase-induced experimental aneurysms in rats. Circulation 1990;82:973-981. ANIDJAR S, DOBRIN PB, EICHORST M, et al. Correlation of inflammatory infiltrate with the enlargement of experimental aortic aneurysm. J Vasc Surg 1992 (in press). DOBRIN PB. Mechanical properties of arteries. Physiological Review I978;58:397-460. L E F E V R E M, RUCKER RB. Aorta elastin turn-over in normal and hypercholesterolemic Japanese quail. Biochem Biophys Acta 1980;630:51%529. MC MAHON MP, FARIS B, WOLFE BL. Aging effects on the elastin composition in the extracellular matrix of cultured rat aortic smooth muscle cells. In Vitro Cell Dev Biot 1985;21:674--680. FRANCOMANO CA, STREETEN EA, MEYERS DA, et al. Marfan syndrome: exclusion of genetic linkage to three major collagen genes. A m J Med Genet 1988;29:457-462. KIRN TF. Marfan's syndrome starting to yield secrets (news). J A M A 1988;260:3108. MC KISICK VA. The defect in Marfan syndrome. Nature 1991;352:279-281. SAKAI LY, K E E N E DR, E N G V A L L E. Fibrillin, a new 350-kD glycoprotein is a component of extracellular microfibrils. J Cell Biol 1986;103:2499-2509.

ANNALS OF VASCULAR SURGERY

68. KONTUSAARI S, TROMP G, KUIVANIEMI, et al. A mutation in the gene for type III procollagen (COL3AI) in a family with aortic aneurysms. J Clin Invest 1990;86:14651473. 69. POPE FM, MARTIN GR, MC KUSICK VA. Patients with type IV EDS lack type III collagen. Proc Natl Acad Sci (USA) 1975;72:1314-1317. 70. BARABAS AP. Vascular complications of the EhlersDanlos syndrome. J Cardiovasc Surg 1972;13:160-163. 71. LEA THOMAS M. Arteriomegaly. Br J Surg 1971;58:690694. 72. HOLLIER LH, STANSON AW, GLOVICZKI P, et al. Arteriomegaly: classification and morbid implications of diffuse aneurysmal disease, Surgery 1983;93:700-708. 73. CALLUM KG, LEA THOMAS M, BROWSE NL. A definition of arteromegaly and the size of arteries supplying the lower limbs. Br J Surg 1983;70:524-529. 74. CARLSON DH, GRYSKA P, SELETZ J, et al. A JR 1975 ;125:553-558. 75. RANDALL PA, OMAR MM, ROHMER R, et al. Arteria magna revisited. Radiology 1979;132:295-300. 76. BUSUTILL RW, RINDERBRIECHT H, FLESHER A. Elastase activity: the role of elastase in aortic aneurysm formation. J Surg Res 1982;32:214-217. 77. WERB Z, BANDA ML, MC KERROW JH. Elastases and elastin degradation. J Invest Dermatol t982;79:154S-159S. 78. REIKO T, WERB Z. Secretory products of macrophages and their physiological functions. A m J Physiol 1984;246: CI-C9. 79. BEITH JG. Elastase: catalytic and biological properties. In: MECHAM RP (ed). Regulation o f Matrix Accumulation. New York: Academic Press, 1986, pp 217-320. 80. BECKMAN EN. Plasma cell infiltrates in atherosclerotic abdominal aortic aneurysms. A m J Clin Pathol 1986;85:2124. 81. ROSE AG, DENT DM. Inflammatory variants of abdominal aortic aneurysms. Arch Path Lab Med 1981;105:40% 413. 82. KOCH AE, HAINES GK, RIZZO RJ, et al. Human abdominal aortic aneurysms, lmmunophenotypic analysis suggesting an immunemediated response. A m J Pathol 1990;137:1199-1213. 83. MECHAM RP, LANGE G. Antigenicity of elastin: characterization of major antigenic determinants on purified insoluble elastin. Biochemistry 1982;21:669-673. 84. BAYDANOFF S, NICOLOFF G, ALEXIEV C. Agerelated changes in antielastin antibodies in serum from normal and atherosclerotic subjects. Atherosclerosis 1987; 63:267-271. 85. CANNON D J, READ RC. Blood elastolytic activity in patients with aortic aneurysm. Ann Thorac Surg 1982;34: 10-15. 86. ROUIS M, NIGON F, LAFUMA C. Expression ofelastase activity by human monocyte-macrophage is modulated by cellular cholesterol content, inflammatory mediators and phobol myristate acetate. Arteriosclerosis 1990;10:246-255. 87. HARTUNG HP, KLADETZKY RG, HENNERICI M. Chemically modified low density lipoproteins as inducers of enzyme release from macrophages. FEBS Letter 1985;186: 2t 1-214. 88. KELLEY JL, ROZEK MM, SUENRAM CA. Activation of human peripheral blood monocytes by lipoproteins. Am J Pathol 1988;130:223-231. 89. ROUIS M, NIGON F, CHAPMAN MF. Platelet activating factor is a potent stimulant of the production of active oxygen species by human monocyte-derived macrophages. Biochem Biophys Res Commun 1988;156:t293-1301. 90. GOWN A, TSUKADA T, ROSS R. Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. A m J Pathol I986;125:191-207. 91. JONASSON L, HOLM J, SKALLI O. Regional accumu-

VOLUME 6 No 3 - 1992

92.

93.

94.

95.

96.

97. 98. 99.

100,

101. 102.

103. 104. 105. 106. 107.

PATHOGENESIS OF ACQUIRED AAA

lation of T cells, macrophages and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 1986;6: 131-138. GRANSTEIN RD, MURPHY GF, MARGOLIS RJ. Gamma-interferon inhibits collagen synthesis in vivo in the mouse. J C/in Invest 1987;79:1254-1258. GERTZ SD, KURGAN A, EISENBERG D. Aneurysm of the common carotid artery induced by periarterial application of calcium chloride in vivo. J C/in Invest 1988;81:649656. FLECKENSTEIN A, FREY M, ZORN J. The role of calcium in the pathogenesis of experimental arteriosclerosis. TIPS 1987;8:496-501. TILSON MD. Decreased hepatic copper levels: a possible chemical marker for the pathogenesis of aortic aneurysms in humans. Arch Surg 1982;117:1212-1213. TILSON MD, DAVIS G. Deficiencies of copper and a compound with ion-exchange characteristics of pyridinoline in skin from patients with abdominal aortic aneurysms. Surgery 1983;94:134-14t. LALICH JJ. Aortic aneurysms in experimental lathyrism. Arch Pathol 1967;84:528-535. BARROW MV, SIMPSON CF, MILLER EJ. Lathyrism: a review. Q Rev Bio/1974;49:101-128. ALLEN KGD, KLEVAY LM. Cholesterolemia and cardiovascular abnormalities in rats caused by copper deficiency. Atherosc/erosis 1978;29:81-93. TINKER D, RUCKER RB. Role of selected nutrients in synthesis, accumulation, and chemical modification of connective tissue proteins. Physio/Rev 1985;65:607-657. JOHANSEN K, KOEPSELL T. Familial tendency for abdominal aortic aneurysms. JAMA 1986;256:1934-1936. NORRGARD O, ANGQUIST KA, RAIS O. Familial occurrence of abdominal aortic aneurysms. Surgery 1984;95: 6504556. ANDREWS EJ, WHITE WJ, BULLOCK LP. Spontaneous aortic aneurysms in blotchy mice. A m J Patho/ 1975; 78:199-210. BORKETT-JONES HJ, STEWART G, CHILVERS AS. Abdominal aortic aneurysms in identical twins. J Roy Soc Med 1988;81:471-472. COLE CW. Highlights of an international workshop on abdominal aortic aneurysms. Can Med Assoc J 1989;141: 393-395. LOOSEMORE TM, CHILD AH, DORMANDY JA. Familial abdominal aortic aneurysms. J Roy Soc Med 1988; 81:472-473. VICTOR DW, MC CREADY RA, HYDE GL. The role of

108. 109. 110. 111. 112. 113.

114. 115.

116. 117.

118.

119.

120.

121. 122.

SeNSe

305

inheritance in the pathogenesis of abdominal aortic aneurysm. J Ken Med Assoc 1985;4:601--602. CLIFTON MA. Familial abdominal aortic aneurysms. Br J Surg 1977;64:765-766. TILSON MD, SEASHORE MR. Human genetics of the abdominal aortic aneurysm. Surg Gynecol Obstet 1984;158: 12%132. TILSON MD, SEASHORE MR. Fifty families with abdominal aortic aneurysms in two or more first-order relatives. Am J Surg 1984;147:551-553. POWELL JT, GREENHALGH RM. Multifactorial inheritance of abdominal aortic aneurysm. Eur J Vasc Surg 1987;1:29-31. BOWERS D, CANE WS. Aneurysms of the abdominal aorta: a 20 years study. J Roy Soc Med 1985;78:812-820. BENGTSSON H, NORRGARD O, ANGQUIST KA, et al. UItrasonographic screening of the abdominal aorta among siblings of patients with abdominal aortic aneurysms. Br J Surg 1989;76:589-591. WEBSTER MW, ST JEAN PL, STEED DL, et al. Abdominal aortic aneurysm: results of a family study. J Vasc Surg 1991 ;13:366--372. WEBSTER MW, FERRELL RE, ST JEAN PL, et al. Ultrasound screening of first-degree relatives of patients with an abdominal aortic aneurysm. J Vasc Surg 1991;13: 9-14. NORRGARD O, CEDERGREN B, ANGQUIST KA, et al. Blood groups and HLA antigens in patients with abdominal aortic aneurysms. Hum Hered 1984;34:9-13. NORRGARD O, BECKMAN G, CEDERGREN B. HLA antigens, blood groups and serum protein groups in patients with intermittent claudication, t t u m Hered 1989;39:192195. NORRGARD O, FROHLANDER N, BECKMAN G, et al. Association between haptoglobin groups and aortic abdominal aneurysms. Hum Hered 1984;34:166-169. NORRGARD O, ANGQUIST KA, JOHNSON O. Familial aortic aneurysms-serum concentrations of triglyceride, cholesterol, HDL-cholesterol and (VLDL +LDL)-cholesterol. Br J Surg 1985;72:113-116. NORRGARD O, ANGQUIST KA, DAHLEN G. High concentrations of Lp(a) lipoprotein in serum are common among patients with abdominal aortic aneurysms. Intern Angio/ 1988;7:46-50. AUERBACK O, GARFINKEL L. Atherosclerosis and aneurysm of aorta in relation to smoking habits and age. Chest 1980;78:805-809. SPITTELL JA Jr. Hypertension and arterial aneurysm. J A m Co//Cardio/ 1983;1:533-540.